Findings

This mutation was first detected in a Caucasian patient of Spanish or Portuguese ancestry who was diagnosed with probable Alzheimer's disease according to DSM-IV and NINCDS-ADRDA criteria. Clinical symptoms began at age 31 and the patient died two years later. The patient had a family history of AD, although it was not possible to evaluate segregation of the mutation with disease (Guerreiro et al., 2010).

This mutation was later reported in two members of a Kurdish family affected by a familial dementia syndrome described as reminiscent of Creutzfeldt-Jakob disease because it involved prominent cerebellar ataxia and other motor features in addition to rapid cognitive decline (Sieczkowski et al., 2015). The reported pedigree shows five affected family members over four generations. The proband developed symptoms at age 47, starting with gait disturbance and uncoordinated jerky movements of the right arm. He had a three-year history of severe depression. Within one year of developing motor symptoms, he developed rapid cognitive decline and dementia. He developed seizures and was bedridden at age 49. He died at age 55. His brother had died at age 37 with a diagnosis of CJD following a similar disease course. No autopsy was performed. The proband’s mother had died in her 30s with dementia, but further clinical details were not available. The proband’s niece, who also carried the mutation, showed signs of cognitive decline at the time of the report.

In the Kurdish proband, a detailed neuropathological examination revealed extensive amyloid, tau, and α-synuclein pathology, but no deposits of TDP-43, FUS, or PrP. Amyloid pathology consisted of abundant cored and diffuse plaques throughout the cortex in addition to some cerebral amyloid angiopathy in the vasculature (CERAD stage C). Notably, N-truncated pyroglutamate-modified Aβ peptides were observed, including within Purkinje cells. Tau pathology consisted of neurofibrillary tangles, dystrophic neurites, and neuropil threads, especially prominent in the neocortex, hippocampal formation, and thalamus (Braak stage VI). Alpha-synuclein pathology was most prominent in the amygdala, temporal cortex, hippocampal formation, brainstem, and basal ganglia. The abundant Lewy body pathology in these regions was consistent with Parkinson's disease stage 6 (Braak et al., 2003) and fulfilled criteria for dementia with Lewy bodies (McKeith et al., 2005). Spongiosis was also observed in the superficial layers of the frontal and parietal cortices along with reactive astrogliosis (Sieczkowski et al., 2015).

Biological Effect

Many years before this mutation was detected in a patient, an I to F amino acid change at this position was shown experimentally to affect APP cleavage by γ-secretase. Specifically, it was shown that when the isoleucine residue was altered to phenylalanine, the amino acid change, referred to as I45F, affected γ-secretase cleavage specificity and caused a dramatic increase in the Aβ42/Aβ40 ratio (Lichtenthaler et al., 1999). Consistent with this effect on Aβ production, an elevated Aβ42/Aβ40 ratio was reported in CHO cells as well as increased APP C-terminal fragments and decreased APP intracellular domain production (Herl et al., 2009; Guardia-Laguarta et al., 2010).

Research Models

This mutation has been introduced into several AD mouse models, including two knock-in models (APPNL-F and APPNL-G-F). The presence of the I716F mutation in these models significantly increases the ratio of Aβ42 to Aβ40. These knock-in mice, which also harbor additional APP mutations, develop amyloid plaques, gliosis, and cognitive impairment, but not tangles or neurodegeneration. They are considered advantageous models for studying the effects of pathological levels of Aβ in the context of physiological levels of APP.